Rac3 induces a molecular pathway triggering breast cancer cell aggressiveness: differences in MDA-MB-231 and MCF-7 breast cancer cell lines.
Rac3 induces a molecular pathway triggering breast cancer cell aggressiveness: differences in MDA-MB-231 and MCF-7 breast cancer cell lines.
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DOI：
10.1186/1471-2407-13-63
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发表时间：
2013-02-06
期刊：
影响因子：
3.8
通讯作者：
Soria C
中科院分区：
文献类型：
--
作者：
Gest C;Joimel U;Huang L;Pritchard LL;Petit A;Dulong C;Buquet C;Hu CQ;Mirshahi P;Laurent M;Fauvel-Lafève F;Cazin L;Vannier JP;Lu H;Soria J;Li H;Varin R;Soria C
Rho GTP酶参与与癌症相关的细胞功能。RhoA和Rac 1的作用已经确定。然而，Rac 3在癌症侵袭性中的作用还不太清楚。进行这项工作以分析Rac 3在两种乳腺癌细胞系MDA-MB-231和MCF-7的侵袭性中的意义：两者都表达Rac 3，但MDA-MB-231表达更多活化的RhoA。还将Rac 3在癌细胞中的作用与其对非致瘤性乳腺上皮细胞MCF-10A的作用进行了比较。我们分析了通过抗Rac 3 siRNA的Rac 3消耗的后果。首先，我们分析了Rac 3缺失对乳腺癌细胞侵袭性的影响。在侵袭性MDA-MB-231细胞中，Rac 3抑制导致侵袭性（40%）和细胞与胶原蛋白的粘附（84%）显著降低，伴随着TNF诱导的凋亡增加（72%）。这表明Rac 3参与了癌细胞的侵袭性。其次，我们研究了Rac 3抑制对相关信号分子NF-κB和ERK表达和活化的影响。还分析了细胞因子分泌谱。在非侵入性MCF-7系中; Rac 3不影响任何攻击性参数。Rac 3敲低在两种细胞系中的作用之间的差异可以解释如下：在MDA-MB-231系中，癌细胞的Rac 3依赖性侵袭性是由于Rac 3/ERK-2/NF-κB信号传导途径，其负责MMP-9、白介素-6、-8和GRO分泌，以及对TNF诱导的细胞凋亡的抗性，而在MCF-7系中，由于这些细胞中NF-κB亚基的低表达，该途径没有功能。Rac 3可能是抑制侵袭性乳腺癌的有效靶点。
Rho GTPases are involved in cellular functions relevant to cancer. The roles of RhoA and Rac1 have already been established. However, the role of Rac3 in cancer aggressiveness is less well understood. This work was conducted to analyze the implication of Rac3 in the aggressiveness of two breast cancer cell lines, MDA-MB-231 and MCF-7: both express Rac3, but MDA-MB-231 expresses more activated RhoA. The effect of Rac3 in cancer cells was also compared with its effect on the non-tumorigenic mammary epithelial cells MCF-10A. We analyzed the consequences of Rac3 depletion by anti-Rac3 siRNA. Firstly, we analyzed the effects of Rac3 depletion on the breast cancer cells’ aggressiveness. In the invasive MDA-MB-231 cells, Rac3 inhibition caused a marked reduction of both invasion (40%) and cell adhesion to collagen (84%), accompanied by an increase in TNF-induced apoptosis (72%). This indicates that Rac3 is involved in the cancer cells’ aggressiveness. Secondly, we investigated the effects of Rac3 inhibition on the expression and activation of related signaling molecules, including NF-κB and ERK. Cytokine secretion profiles were also analyzed. In the non-invasive MCF-7 line; Rac3 did not influence any of the parameters of aggressiveness. This discrepancy between the effects of Rac3 knockdown in the two cell lines could be explained as follows: in the MDA-MB-231 line, the Rac3-dependent aggressiveness of the cancer cells is due to the Rac3/ERK-2/NF-κB signaling pathway, which is responsible for MMP-9, interleukin-6, -8 and GRO secretion, as well as the resistance to TNF-induced apoptosis, whereas in the MCF-7 line, this pathway is not functional because of the low expression of NF-κB subunits in these cells. Rac3 may be a potent target for inhibiting aggressive breast cancer.
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影响因子：
4.8
作者：
Haataja, L;Groffen, J;Heisterkamp, N
通讯作者：
Heisterkamp, N
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2
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Symons, M
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5.3
作者：
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Heisterkamp, N